NSAID Determination

Arabian Journal of Chemistry (2013) 6, 145163
King Saud University
Arabian Journal of Chemistry

www.ksu.edu.sa
www.sciencedirect.com
REVIEW ARTICLE
Spectrophotometric and spectrouorometric methods

for the determination of non-steroidal anti-inammatory
drugs: A review
Ayman A. Gouda a,*, Mohamed I. Kotb El-Sayed b, Alaa S. Amin c,
Ragaa El Sheikh a
a
b
c
Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt

Organic Chemistry Department (Pharmaceutical Biochemistry), Faculty of Pharmacy, Sanaa University, Sanaa, Yemen
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
Received 27 June 2010; accepted 6 December 2010

Available online 13 December 2010
KEYWORDS
Review;
Non-steroidal
anti-inammatory;
Spectrophotometry;
Spectrouorometry
Abstract Non-steroidal anti-inammatory drugs (NSAIDs) are the group most often used in
human and veterinary medicine, since they are available without prescription for treatment of fever
and minor pain. The clinical and pharmaceutical analysis of these drugs requires effective analytical
procedures for quality control and pharmacodynamic and pharmacokinetic studies. An extensive
survey of the literature published in various analytical and pharmaceutical chemistry related journals has been conducted and the instrumental analytical methods which were developed and used
for determination of some non-steroidal anti-inammatory, coxibs, arylalkanoic acids, 2-arylpropionic acids (profens) and N-arylanthranilic acids (fenamic acids) in bulk drugs, formulations and
biological uids have been reviewed. This review covers the time period from 1985 to 2010 during
which 145 spectrophotometric methods including UV and derivative; visible which is based on formation of metal complexation, redox reactions, ion pair formation, charge-transfer complexation
and miscellaneous; ow injection spectrophotometry as well as spectrouorometric methods were
* Corresponding author. Tel.: +2 055 242 3346; fax: +2 055 230

8213.
E-mail address: aymangouda77@gmail.com (A.A. Gouda).
1878-5352 2011 King Saud University. Production and hosting by
Elsevier B.V. All rights reserved.
Peer review under responsibility of King Saud University.
doi:10.1016/j.arabjc.2010.12.006
Production and hosting by Elsevier
146
A.A. Gouda et al.

reported. The application of these methods for the determination of NSAIDs in pharmaceutical formulations and biological samples has also been discussed.
2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Spectrophotometric and spectrouorometric methods for determination of coxibs. . . . . . . . . . . . . . . . . . . . . . . . . . 148
2.1. Celecoxib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
2.2. Valdecoxib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
2.3. Rofecoxib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
2.4. Etoricoxib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Spectrophotometric and spectrouorometric methods for determination of arylalkanoic acids . . . . . . . . . . . . . . . . . 150
3.1. Aceclofenac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
3.2. Diclofenac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
3.3. Etodolac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
3.4. Ketorolac. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Spectrophotometric and spectrouorometric methods for determination of N-arylanthranilic acids derivatives (fenamic
acids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.1. Mefenamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
4.2. Flufenamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.3. Enfenamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
4.4. Tolfenamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Spectrophotometric and spectrouorometric methods for determination of arylpropionic acids (profens) . . . . . . . . . 159
5.1. Ibuprofen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
5.2. Ketoprofen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.3. Flurbiprofen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.4. Naproxen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.5. Tiaprofenic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
1. Introduction
Non-steroidal anti-inammatory drugs (NSAIDs) are a group
of drugs of diverse chemical composition and different therapeutic potentials having a minimum of three common features:
identical basic pharmacological properties, similar basic mechanism of action as well as similar adverse effects. Moreover, all
drugs in this group exhibit acidic character. Most NSAIDs are
weak acids, with a pKa values in the range of 3.05.0 (acids of
medium strength).
NSAID molecules contain hydrophilic groups (carboxylic

or enolic group) and lipophilic ones (aromatic ring, halogen
atoms). In accordance with their acidic character, NSAIDs occur in the gastric juice in the protonated (lipophilic) form. Also
in the small intestine, there are conditions favorable for
absorption of weak acids. NSAID exist in highly ionized forms
in plasma. Low values dening NSAIDs distribution volume
Abbreviations: NSAIDs, non-steroidal anti-inammatory drugs; COX, cyclooxygenase; HPLC, high-performance liquid chromatography; RPHPLC, reversed phase high-performance liquid chromatography; LC, liquid chromatography; TLC, thin layer chromatography; GC, gas
chromatography; IR, infrared; AAS, atomic absorption spectrophotometry; NMR, nuclear magnetic resonance; 1H NMR, proton nuclear
magnetic resonance; MS, mass spectrometry; FIA, ow injection analysis; CE, capillary electrophoresis; r, correlation coefcient; R, intensity ratio;
CZE, capillary zone electrophoresis; MEKC, micellar electrokinetic capillary chromatography; UV, ultraviolet; k, wavelength; Abs, absorbance;
LOD, limit of detection; LOQ, limit of quantitation; mol L1, concentration; 1D, rst derivative spectrophotometry; 1DD, rst derivative of the
ratio spectra; SD, standard deviation; RSD, relative standard deviation; SPE, solid-phase extraction; T1/2, half life time; K, reaction rate constant;
MBTH, 3-methyl-2-benzothiazolinone hydrazone hydrochloride; 3D, third-derivative spectrophotometry; PDAC, p-dimethylaminocinnamaldehyde; DPPH, 2,2-diphenyl-1-picrylhydrazyl; DPPH2, 2,2-diphenyl-1-picrylhydrazine; PDAB, p-dimethylaminobenzaldhyde; TG, thermogravimetry; DSC, differential scanning calorimetry; TIC, 1,3,3-trimethyl-5-thiocyanato-2-[3-(10 ,30 ,30 -trimethyl-30 -H-indol-20 -ylidene)-propenyl]-indolium
chloride; p-chloranil, tetrachloro-p-benzoquinone; DCNP, 2,4,dichloro-6-nitrophenol; o-phen, o-phenanthroline; Bipy, bipyridyl; CT, charge
transfer; TCNE, tetracyanoethylene; DDQ, 2,3-dichloro-5,6-dicyano-p-benzoquinone; DCNP, 2,4,dichloro-6-nitrophenol; 2D, second-derivative
spectrophotometry; PLS, partial least squares regression; GA-PLS, genetic algorithm-partial least squares regression; l, ionic strength; a-CD,
a-cyclodextrin; b-CD, b-cyclodextrin; DH, enthalpy change; DS, entropy change; DG, free energy change; IUPAC, international union of pure
and applied chemistry; PHP, phenolphthalein.

(from 0.1 to 1.0) in tissues may be a proof of poor distribution
of these drugs in extra vascular systems. A very high degree of
binding with plasma proteins (>97%) is the result of favorable
amiliphilic properties and accounts for the fact of displacing
other drugs from protein binding of NSAIDs. Most NSAIDs
are metabolized in the liver by oxidation and conjugation to
inactive metabolites which are typically excreted in the urine,
although some drugs are partially excreted in bile. Metabolism
may be abnormal in certain disease states, and accumulation
may occur even with normal dosage (Starek and Krzek, 2009).
NSAIDs are classied according to their chemical structure
into the following groups: salicylic acid derivatives (i.e. acetylsalicylic acid, salicylamid, sodium salicylate); aniline and
p-aminophenol derivatives (i.e. paracetamol, phenacetyne);
pyrazolone derivatives (i.e. phenylbutazone, propyphenazone);
oxicams (i.e. piroxicam, meloxicam, tenoxicam, lornoxicam,
droxicam); arylalkanoic acids derivatives (i.e. aceclofenac,
diclofenac, etodolac, indometacin, nabumetone, sulindac,
tolmetin); 2-arylpropionic acids derivatives (profens) (i.e. urbiprofen, ibuprofen, ketoprofen, naproxen, tiaprofenic acid);
N-arylanthranilic acids (fenamic acids) (i.e. mefenamic acid,
tolfenamic acid, ufenamic acid, meclofenamic acid); enolic
acid derivatives, and coxibs (i.e. celecoxib, rofecoxib, etoricoxib, parecoxib, valdecoxib); naphtylbutanone derivatives (nabumetone); sulphonamides (nimesulide); benzoxazocine
derivatives (nefopam). Four groups of NSAIDs only were chosen in the present work due to more spectrophotometric and
spectroourometric methods done.
Most NSAIDs act as non-selective inhibitors of the enzyme
cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1)
and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase
catalyzes the formation of prostaglandins and thromboxane
from arachidonic acid (itself derived from the cellular
phospholipid bilayer by phospholipase A2). Prostaglandins
act (among other things) as messenger molecules in the process
of inammation.
NSAIDs are easily available and effective and thus are
extensively used by patients. The growing demand for these
agents stimulate a search for new even more effective drugs,
but also calls for higher level of quality control of these therapeutic substances and preparations, so that they are in the
highest possible degree free from any impurities that may come
from the production process, as well as from decomposition
products of active or auxiliary substances. Therefore, it seems
appropriate to develop new analytical methods regarding their
qualitative and quantitative analysis (Sherma, 2000; Rao et al.,
2005; Ferenczi-Fodor et al., 2001).
The progress of analytical chemistry in the scope of instrumentalisation of the methods of chemical analysis is reected
in the use thereof in pharmacopoeia monographs as well as in
the standards adopted by manufacturers. A constant place is
occupied by chromatographic methods [high-performance liquid chromatography (HPLC), thin layer chromatography
(TLC), and gas chromatography (GC)]. Unication of the
equipment used necessitates preparation of a very accurate
and detailed description of conditions for carrying out the analysis. Other meaningful methods having a big meaning are also
ultravioletvisible (UVvis) and infrared (IR) spectrophotometry, atomic absorption spectrophotometry (AAS), nuclear
magnetic resonance (NMR), mass spectrometry (MS) or
spectrouorometry. Among the analytical methods used for
determining NSAIDs are also electromigrational (capillary
147
electrophoresis (CE), capillary zone electrophoresis (CZE),
and micellar electrokinetic capillary chromatography (MEKC))
and voltamperometric methods. One that has been gaining
more and more applications is the ow injection analysis
(FIA), whose main advantage is the full automation of the analysis, which considerably minimizes the effects of side reactions
and thus increases the sensitivity and selectivity of this method.
Introduction of new methods, enabling carrying out determinations with maximum accuracy, contributes to increased
interest in analytical methods as such. They should enable to
simultaneously determine the individual components in multicomponent preparations and in biological material. Range of
guidelines, standardizing requirements concerning the quality
of drugs, have been issued. Fulllment conrms them the
appropriate quality of the product and of the analytical method used. These are numerical parameters that validate reliability of the results and enable comparing efciency of the
methods used. The process that is used to determine the above
parameters is the so-called method validation (Harmonised
Tripartite Guideline, 1996).
Development and validation of analytical methods are of
basic importance to optimize the analysis of drugs in the pharmaceutical industry and to guarantee quality of the commercialized product. Several techniques like AAS (Khuhawar
et al., 2001; Salem et al., 2000, 2001; Alpdogan and Sungur,
1999), HPLC (Hassan et al., 2008; Pavan Kumar et al.,
2006; Jaiswal et al., 2007; Vinci et al., 2006; Sun et al., 2003),
SPE-LC (Hirai et al., 1997), LC (Rouini et al., 2004), GC
(Thomas and Foster, 2004; El Haj et al., 1999; Gonzalez
et al., 1996), CE (Makino et al., 2004; Ahrer et al., 2001; Perez-Ruiz et al., 1998), potentiometric (Santini et al., 2007), conductometric (Aly and Belal, 1994) and voltammetric methods
(Liu and Song, 2006) have been used for the determination
of NSAIDs. Chromatographic methods have been extensively
used and recommended. However, these methods generally require complex and expensive equipment, provision for use and
disposal of solvents, labour-intensive sample preparation procedures and personal skills in chromatographic techniques.
Spectrophotometric and spectrouorometric methods for
the determination of drugs can be used in laboratories where
modern and expensive apparatuses such as that required for
GLC or HPLC are not available. However, spectrophotometric and spectrouorometric methods are versatile and economical particularly for developing countries. Spectrophotometric
and spectrouorometric methods have several advantages such
as being easy, less expensive and less time consuming compared with most of the other methods. Spectrophotometric
and spectrouorometric methods are simple and rapid; so
these methods can be successfully used for pharmaceutical
analysis, involving quality control of commercialized product
and pharmacodynamic studies. These methods are mostly
based on the formation of coloured complexes between NSAIDs and the reagent which can be determined by visible spectrophotometry. The complexes formed are mostly due to
charge transfer reaction between the drug and the reagent or
due to formation of ion-pair complexes. The spectrophotometric methods are simple and rapid but less sensitive. UV- and
derivative spectrophotometric methods have also been widely
used for NSAIDs and are covered under this review.
In the last few years, there was no review published covering all different spectrophotometric techniques like (ion pair,
charge transfer, metal complexes, ow injection, derivative)
148
used for the determination of NSAIDs. The high importance
of this class of drugs prompted us to review the most important recent spectrophotometric methods for their analysis in
pure forms, in different pharmaceutical dosage forms and in
biological uids reported so far in the literature. Because of
the large number of references that appeared as individual
methods or as part of clinical and pharmacological studies, it
is possible to make reference only to the most important papers. The present review comprises references covering the period from 1985 to 2010.
2. Spectrophotometric and spectrouorometric methods for

determination of coxibs
2.1. Celecoxib
The ofcial method of celecoxib was potentiometric titration
method with perchloric acid (Pharmacopoeia, 2004).
UV spectrophotometric methods have been developed for
the determination of celecoxib and tizanidine hydrochloride in
its pure and in its pharmaceutical formulations. Celecoxib having absorption maximum at 251.2 nm in 0.1 mol L1 sodium
hydroxide (Sankar, 2001). New UV spectrophotometric methods for the quantitative estimation of celecoxib, a selective
COX-2 inhibitor, in pure form and in solid dosage form were
developed in the present study. The linear regression equation
obtained by least square regression method, was Abs = 4.949
102. Conc. (lg mL1) + 1.110 102. The detection limit was
found to be 0.26 lg mL1 (Saha et al., 2002). Ultraviolet spectrophotometric method for the determination of celecoxib in
bulk and its pharmaceutical formulation (dispersible tablets
and capsules) has been developed. The absorbance maxima of
celecoxib in a mixture of methanol and 0.01 N sodium hydroxide (1:1 v/v) were determined at 253.1 nm. Beers law is obeyed
over concentration range of 822 lg mL1 with correlation
coefcient r > 0.999 (Sahu et al., 2009).
Two simple and sensitive spectrophotometric methods have
been developed for the quantitative estimation of celecoxib
from its capsule formulation. The rst method is a UV spectrophotometric method using methanol as solvent; the drug
showed absorption maximum at 253.2 nm in methanol and linearity was observed in the concentration range of 5.0
15 lg mL1. The second method is a visible spectrophotometric method, based on formation of red coloured complex of
drugs with o-phenanthroline and ferric chloride, the complex
showed absorbance maximum at 509.2 nm and linearity was
observed in the concentration range of 50400 lg mL1 (Pillai
and Singhvi, 2006).
A simple uorescence method was developed for the direct
determination of celecoxib in capsules. The capsules were emptied, pulverized and dissolved in either ethanol or acetonitrile,
sonicated and ltered. Direct uorescence emission was measured at 355 5 nm (exciting at 272 nm). The method was
fully validated and the recoveries were excellent, even in presence of excipients (Damiani et al., 2003).
2.2. Valdecoxib
The ofcial method of valdecoxib was potentiometric titration
A.A. Gouda et al.

Two simple, rapid, accurate and economical methods have
been developed for the estimation of valdecoxib and tizanidine
HCl in the mixture. Valdecoxib has an absorbance maximum
at 243 nm in methanol: 0.1 mol L1 HCl (1:1) mixture. The linearity was observed in the concentration range 5.0
30 lg mL1. First method is based on Q absorbance ratio
and second method is based on the simultaneous equations
(Sankar et al., 2007). Two methods for simultaneous estimation of valdecoxib and tizanidine in combined dosage form
have been described. The rst method; involves formation of
Q-absorbance equation at 239.6 (isoabsorptive point) and at
241 nm, while the second method; involves formation of simultaneous equation at 241 and 229 nm, using methanol as solvent (Devarajan and Sivasubramanian, 2006). A reproducible
method for simultaneous estimation of valdecoxib and paracetamol in two-component tablet formulation has been developed. The method of analysis is derivative spectroscopy to
eliminate spectral interference by measuring analytical signals
or dA/dk value at 284 nm (Aditya et al., 2006). Analytical
method for the simultaneous estimation of valdecoxib and paracetamol in combined tablet dosage form by Vierodts UV
spectrophotometric method was validated. The kmax value of
valdecoxib in 0.1 mol L1 NaOH was 244 nm. Beers law is valid in the concentration range of 1.06.0 lg mL1. The A1%
1 cm values for valdecoxib at 244 nm were 520 and 420
(Nagulwar et al., 2006). UV spectrophotometric method has
been developed for the simultaneous estimation of valdecoxib
and tizanidine in pharmaceutical dosage form. The proposed
method is based on the Vierodts simultaneous equations. Valdecoxib absorption maxima at 239.0 nm in methanol. The linearity was observed in the concentration range of 2
18 lg mL1 (Sharma et al., 2009). UV method was used for
bulk form as well as the formulation of the valdecoxib and
was expanded to study the dissolution prole of valdecoxib
tablets. The measurements were done at 241 nm, linear concentration range was observed to be 317 lg mL1. The percentage recovery was found to be between 99.52 and 100.32
(Baviskar et al., 2009).
A spectrophotometric method has been developed for the
determination of valdecoxib in pure and pharmaceutical dosage forms. The method is based on the reaction of valdecoxib
with potassium permanganate to form a bluish green coloured
chromogen with an absorption maximum at 610 nm. Beers
law was obeyed in the range of 5.025 lg mL1. The molar
absorpitivity is 7.1437 103 L mol1 cm1 (Suganthi et al.,
2006).
2.3. Rofecoxib
The ofcial method of rofecoxib was potentiometric
titration method with perchloric acid (Pharmacopoeia,
2004).
Two different UV spectrophotometric methods were developed for the determination of rofecoxib in bulk form and in
pharmaceutical formulations. The rst method, a UV spectrophotometric procedure, was based on the linear relationship
between the rofecoxib concentration and the kmax amplitude
at 279 nm. The second one, the rst derivative spectrophotometry, was based on the linear relationship between the rofecoxib concentration and the rst derivative amplitude at 228, 256
and 308 nm. Calibration curves were linear in the concentration
range using peak to zero 1.535 lg mL1 (Erk and Altuntas,

2004). Rofecoxib has been determined in the presence of
its photo-degradation product using rst derivative spectrophotometry (1D) and rst derivative of the ratio spectra
(1DD) by measuring the amplitude at 316.3 and 284 nm for
1
D and 1DD, respectively. Rofecoxib can be determined in
the presence of up to 70% and 80% of the photo-degradation
product by the 1D and 1DD, respectively. The linearity range
of both the methods was the same (5.826.2 lg mL1) with
mean percentage recovery of 100.08 0.84 and 100.06
1.06 for 1D and 1DD, respectively. 1D method was used to
study kinetics of rofecoxib photo-degradation that was found
to follow a rst-order reaction. The T1/2 was 20.2 min while K
(reaction rate constant) was 0.0336 mol min1 (Shehata et al.,
2004). Rofecoxib was assayed by UV spectrophotometry, the
concentration ranges were 2.030 lg mL1 (Duran et al.,
2004). UV and visible spectrophotometric methods have been
developed for the determination of rofecoxib in pure and its
pharmaceutical formulations. In UV method rofecoxib solution in methanol medium showed absorption maximum at
285 nm, whereas in visible spectrophotometric method it reacts
with ferric chloride and 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) reagent and forms a green coloured chromogen having absorption maximum at 625 nm
(Reddy et al., 2002).
A spectrouorometric method was described to determine
rofecoxib at very low concentrations (25540 ng mL1) where
rofecoxib is converted to its photo-degradate product, which
possesses a native uorescence that could be measured (Shehata et al., 2004).
Table 1
149
2.4. Etoricoxib
The ofcial method of etoricoxib was potentiometric titration
A presented method was performed at 284 nm for the analysis of etoricoxib formulations. Extraction of etoricoxib from
tablet was carried out using methanol. The linearity range
was 5.035 lg mL1 (Shakya and Khalaf, 2007). A simple,
rapid, precise spectrophotometric method for estimation of
etoricoxib in bulk drug, dosage forms and human plasma
was developed. Sample preparation for the developed method
employs 90% methanolic sodium hydroxide (0.1 mol L1) as
the solvent system for analyzing bulk drug and dosage forms,
while precipitation using acetonitrile (direct procedure) and
liquidliquid extraction with ethyl acetate (indirect procedure)
was utilized for its determination in human plasma samples.
All samples were analyzed spectrophotometrically at 280 nm.
For analysis of dosage forms, the method was found to be linear in the range of 3.060 lg mL1 (r2 = 0.9997 and 0.9998);
for estimation of human plasma samples, the method was
found to be linear in the range of 0.120 lg mL1 (r2 =
0.9998 and 0.9994, respectively, for direct and indirect method)
(Vadnerkar et al., 2006). Sensitive UV spectrophotometric
methods for the determination of etoricoxib and ezetimibe
were having absorption maximum at 235 and 230 nm, respectively, and these methods were extended to pharmaceutical
preparations (Sankar et al., 2005). Extractive spectrophotometric methods for the determination of etoricoxib in tablets through ionassociation complexes with bromocresol
Comparison between the spectrophotometric methods for determination of coxibs.
Drug
Method
kmax (nm)
Linear range
(lg mL1)
Ref.
Celecoxib
UV methods
251.2
253.1
253.2
509.2
kem = 355 5
kex = 272
822
5.015
50400
Sankar (2001)
Saha et al. (2002)
Sahu et al. (2009)
Pillai and Singhvi (2006)
Pillai and Singhvi (2006)
Damiani et al. (2003)
243
239.6
241
284
244
239
241
610
5.030
Sankar et al. (2007)

Devarajan and Sivasubramanian (2006)
1.06.0
218
317
5.025
Aditya et al. (2006)

Nagulwar et al. (2006)
Sharma et al. (2009)
Baviskar et al. (2009)
Suganthi et al. (2006)
279, 228, 256 and 308

316.3
284
285
625
1.535
5.826.2
Erk and Altuntas (2004)

Shehata et al. (2004)
2.030
25540 ng/ml
Duran et al. (2004)

Reddy et al. (2002)
Reddy et al. (2002)
Shehata et al. (2004)
284
280
235
416
408
5.035
3.060
Shakya and Khalaf (2007)

Vadnerkar et al. (2006)
Sankar et al. (2005)
Shah et al. (2009)
1,10-Phenanthroline/ferric chloride
Spectrouorometric method
Valdecoxib
UV methods
Potassium permanganate
Rofecoxib
UV methods
Ferric chloride/(MBTH)
Etoricoxib
UV methods
BCG
BCP
150
green (BCG) and bromocresol purple (BCP) were soluble in
chloroform. The complex of etoricoxib with BCG and BCP
showed kmax at 416 and 408 nm, respectively. Molar absorptivity, 1.9331 104 and 1.6642 104 L mol1 cm1 for BCG and
BCP, respectively (Shah et al., 2009).
Table 1 shows comparison between the published spectrophotometric and spectrouorometric methods for coxibs.

determination of arylalkanoic acids
3.1. Aceclofenac
The ofcial method of aceclofenac was potentiometric titration
method with sodium hydroxide (Pharmacopoeia, 2004).
Four procedures for simultaneous estimation of paracetamol and aceclofenac in tablet dosage form have been developed. The rst method employs the formation and solving of
simultaneous equation using 273 nm as the wavelength for
forming equation. The second method employs rst order
derivative spectroscopy to eliminate spectral interference.
The third method employs selection of area under curve in
wavelength region of 271275 nm and solving the equation.
The fourth method employed 266 nm as k1 (isobestic point)
and 244 nm as k2, which is the kmax of paracetamol. The solution of drug in methanol obeys Beers law in the concentration
range 10100 lg mL1 for aceclofenac (Nikam et al., 2007). A
simultaneous equation and Q-analysis UV spectrophotometric
method has been developed for the simultaneous determination of aceclofenac and paracetamol from the combined tablet
dosage form. The method involves solving of simultaneous
equation value analysis based on measurement of absorptivity
at 276, 249 and 270 nm, respectively. Linearity was in the
range 2.025 lg mL1 for aceclofenac (Jain et al., 2007). Three
accurate methods; multicomponent, two wavelength and
simultaneous equations using area under curve have been described for the simultaneous estimation of aceclofenac and
paracetamol in tablet dosage form. Absorption maxima of aceclofenac in methanol diluted with glass double distilled water
was found to be 274.5 nm. Beers law was obeyed in the concentration range 2.020 lg mL1 for aceclofenac (Mahaparale
et al., 2007). A derivative spectrophotometric procedure has
been developed for the simultaneous determination of individual combination of aceclofenac and tramadol with paracetamol in combined tablet preparations. Tablet extracts of the
drugs were prepared in distilled water. The zero crossing point
technique and the compensation technique were used to estimate the amount of each drug in the combined formulations,
and were compared. Calibration graphs are linear
(r = 0.9999), with a zero intercept up to 24 lg mL1 of each
drug in combination with paracetamol. Detection limits at
the p = 0.05 level of signicance were calculated to be
0.5 lg mL1 (Srinivasan et al., 2007). An UV-spectrophotometric method was developed for the estimation of aceclofenac
in tablets. In this method, aceclofenac is determined accurately
having absorbance maximum at 203 nm. Beers law is obeyed
in the concentration range 0.020 lg mL1 (Saravanan et al.,
2006). A spectrophotometric method for the determination
of aceclofenac in its pharmaceutical dosage forms has been
developed. Aceclofenac shows absorption maximum at
273.5 nm and obeyed BeerLamberts law in the concentration
A.A. Gouda et al.

range of 5.045 lg mL1 in the 7.4 phosphate buffer (Dashora
et al., 2006). Two spectrophotometric methods for the determination of aceclofenac and paracetamol in tablets have been
developed. First method is based on the additivity of absorbances. Second method is based on the determination of
graphical absorbance ratio at two selected wavelengths; one
being the isoabsorptive point for the drug (230 nm). Beer
Lamberts law is obeyed in the concentration range 1.0
10 lg mL1 (Mishra and Garg, 2006). New methods for the
determination of aceclofenac in the presence of its degradation
product (diclofenac) were described. Method A utilizes third
derivative spectrophotometry at 242 nm. Method B is a 1DD
spectrophotometric method based on the simultaneous use of
the rst derivative of ratio spectra and measurement at
245 nm. Method C is a pH-induced difference (DA) spectrophotometry using UV measurement at 273 nm. Regression
analysis of a Beers plot showed good correlation in the concentration ranges 5.040, 1040, 1550 lg mL1 for methods
A, B and C, respectively (Hasan et al., 2003). Three methods
were developed for the determination of aceclofenac in the
presence of its degradation product, diclofenac. In the rst
method, third-derivative spectrophotometry (3D) is used. The
3
D absorbance is measured at 283 nm where its hydrolytic
degradation product diclofenac does not interfere. The suggested method shows a linear relationship in the range of
4.024 lg mL1 with mean percentage accuracy of 100.05
0.88. This method determines the intact drug in the presence
of up to 70% degradation product with mean percentage
recovery of 100.42 0.94. The second method depends on
ratio-spectra rst-derivative (RSD1) spectrophotometry at
252 nm for aceclofenac and at 248 nm for determination of
the degradation product over concentration ranges of 4.0
32 lg mL1 for both aceclofenac and diclofenac with mean
percentage accuracy of 99.81 0.84 and 100.19 0.72 for
pure drugs and 100.17 0.94 and 99.73 0.74 for laboratory-prepared mixtures, respectively (El-Saharty et al., 2002).
Two methods have been developed for the quantitative estimation of aceclofenac from tablet formulation using Folin
Ciocalteu reagent. Aceclofenac forms a blue coloured chromogen with the reagent, which shows absorbance maxima at
642.6 nm and linearity in the concentration range of 80
160 lg mL1 of drug (Singhvi and Goyal, 2007). Two convenient visible spectrophotometric methods have been developed
for the estimation of aceclofenac in tablet formulation. The
developed methods are based on the formation of chloroform
extractable complex of aceclofenac with orange G in acidic
medium and naphthol green in aqueous medium. The extracted complex with orange G shows absorbance maxima at
481 nm and linearity in the concentration range of 10
80 lg mL1. The extracted complex with naphthol green
shows absorbance maxima at 633.6 nm and linearity in the
concentration range of 0.21.0 lg mL1 (Goyal and Singhvi,
2006). A spectrophotometric method for the determination
of aceclofenac in its pharmaceutical dosage forms has been
developed. The method is based on the formation of a coloured complex of the drug with ferric nitrate in acidic medium,
which has absorption maximum at 470 nm. Beers law is
obeyed over concentration range of 75200 lg mL1 (Mishra
and Garg, 2006). Quantitative determination of aceclofenac
in pure form and in pharmaceutical formulation was presented. The method is based on the reaction between the drug
via its secondary aromatic amino group and p-dimethylamino-

cinnamaldehyde (PDAC) in acidied methanol to give a stable
coloured complex after heating at 75 C for 20 min. Absorption measurements were carried out at 665.5 nm. Beers law
is obeyed over concentration range 20100 lg mL1 with mean
recovery 100.33 0.84 (Zawilla et al., 2002). A spectrophotometric procedure for the assay of aceclofenac has been
developed. The method is based on the reaction of aceclofenac
with 2,2-diphenyl-1-picrylhydrazyl (DPPH). The latter is
employed to abstract a hydrogen atom from the drug thereby
promoting a process of radical coupling. This results in a
reduction of the violet colour of DPPH with the formation
of the yellow coloured 2,2-diphenyl-1-picrylhydrazine
(DPPH2). The decrease in the intensity of the violet colour is
used to measure the concentration of the drug. All measurements are made at k = 520 nm on methanolic solutions of
the reagent and drugs. Beers law is obeyed in the range of
5.030 lg mL1 (Salem, 2000). A spectrophotometric method
was adopted for the analysis of the anti-inammatory drug,
aceclofenac. The method is based on the formation of coloured
complexes between the drug and p-dimethylaminobenzaldehyde reagent (PDAB) in the presence of sulfuric acid and ferric
chloride. Measurement of the absorbance was carried out at
545.5 nm. Regression analysis of Beers plots showed good
correlation in the concentration ranges 8.055 lg mL1. The
spectrouorometric method in samples of aceclofenac in the
phosphate buffer pH 8.0 showed native uorescence at
k = 355 nm when excitation was at 250 nm. The calibration
graph was rectilinear from 2.0 to 8.0 lg mL1. The proposed
methods are applied successfully for the determination of the
drug in bulk powder with a mean accuracy of 100.03 0.38
in the PDAB method and of 99.88 0.45 in the spectrouorometric method (El Kousy, 1999).
3.2. Diclofenac
The ofcial method of diclofenac was potentiometric titration
Spectrophotometric methods were developed and validated
for quantitation of diclofenac potassium and tizanidine in tablet dosage form. Three new analytical methods were developed
based on the simultaneous estimation of drugs in a binary
mixture without previous separation. In multiwavelength technique, the binary mixture was determined by mixed standards
and three sampling wavelengths of 277, 295 (isobestic point),
and 320 nm. In the simultaneous equation method, the drugs
were determined by using the absorptivity values of diclofenac
potassium at selected wavelength, viz., 277 nm. The standard
deviation value for the validation parameters was found to
be between 0.08% for multiwavelength technique and between
0.069% for simultaneous equation method. The graphical
absorbance ratio method was performed by absorbances at 277,
295 (isobestic point), and 320.4 nm of their mixture (Sanjay
et al., 2006). Spectrophotometric methodology was applied
in order to determine benzyl alcohol and diclofenac in injectable formulations by applying a multivariate calibration method. By a multivariate calibration method such as partial least
squares, it is possible to obtain a model adjusted to the concentration values of the mixtures used in the calibration range. In
this study, the concentration model is based on absorption
spectra in the 230320 nm range for 25 different mixtures of
benzyl alcohol and diclofenac. Calibration matrix contains
1.050 lg mL1 for diclofenac (Ghasemi et al., 2005a). Two
151
spectrophotometric methods were presented for simultaneous
quantitative determination of benzyl alcohol and diclofenac
in various pharmaceutical forms. The rst method makes use
of a derivative of the double-divisor-ratio spectrum of optical
density. The linear determination range is 1245 lg mL1. In
the second method, the analytical signals are measured at
wavelengths corresponding to either maxima or minima for
both drugs in the spectra of the rst derivative of the ratio
of optical densities of the sample and the standard solution
of one of the drugs. In this case, the linear determination
ranges is 1445 lg mL1 (Ghasemi et al., 2005b). A procedure
for determination of diclofenac in the presence of B vitamins
was described, based on UV measurements and partial least
squares. The interference of thiamine and pyridoxine were
modeled using an experimental design constructed in the
ranges of 1050 lmol L1 for diclofenac (Sena et al., 2004).
Spectrophotometric methodology was used in order to determine diclofenac and benzyl alcohol in injectable formulations
by applying, on the one hand, the rst-derivative method of
crossing zero for diclofenac sodium and on the other, the second derivative for benzyl alcohol (De Micalizzi et al., 1998).
Two methods for the determination of the diclofenac salts
[sodium or diethylammonium] in three pharmaceutical formulations (tablets, suppositories and gel) are presented. In the
rst, diclofenac salt is determined both by measuring the
absorbance of the solutions at a xed wavelength (k =
276 nm) and using a multiwavelength computational program
to process the spectrophotometric data in a selected range
(k = 230340 nm). In this case, the analysis is performed measuring the peak-to-peak amplitude in the rst-derivative UV
spectrum (1D 261.296). In the second method, diclofenac is
precipitated in acid medium and determined by the analysis
of the endothermic peak (tp = 182 C) in the DSC curve obtained in nitrogen atmosphere. Finally, some aspects of chemical (solubility, acidbase equilibria, redox reaction),
spectroscopic (UV, IR) and thermoanalytical (TG, DSC)
behaviour of DS and DH and the values of the parameters
which enable to calculate the UV spectrum of DS in aqueous
solution are reported (Bucci et al., 1998). A second derivative
spectrophotometric method (2D) has been developed for the
determination of the degradation products from diclofenac sodium in gel-ointment. The amplitudes in the second derivative
spectra at 260 and 265 nm were selected to determine oxindol.
The LOD of oxindol was estimated to be 0.01% with respect to
the gel-ointment (Karamancheva et al., 1998). Three procedures for simultaneous estimation of diclofenac sodium and
paracetamol in two component tablet formulation have been
developed. The methods employ rst derivative ultraviolet
spectrophotometry, simultaneous equations and the program
in the multicomponent mode of analysis of the instrument
used, for the simultaneous estimation of the two drugs. In
0.02 mol L1 sodium hydroxide, diclofenac sodium has maxima at 276 nm (Bhatia et al., 1996). A procedure for simultaneous estimation of diclofenac sodium, chlorzoxazone and
paracetamol in three component tablet formulations has been
developed. The method is based on the native ultraviolet
absorbance maxima of the three drugs in 0.02 mol L1 sodium
hydroxide. Diclofenac sodium has absorbance maxima at
276 nm (Bhatia and Dhaneshwar, 1995). Spectrophotometric
methods for simultaneous estimation of diclofenac sodium
and rabeprazole in combined dosage form. Methanol was
used as a common solvent for both the drugs. Linearity was
152
observed at both wavelengths in the concentration range of
1050 lg mL1 for each drug (Choudhary et al., 2010).
A new spectrophotometric method has been developed for
the determination of diclofenac sodium in pharmaceutical
preparations. This method is based on the reaction of diclofenac
sodium with an analytical reagent 1,3,3-trimethyl-5-thiocyanato-2-[3-(10 ,30 ,30 -trimethyl-30 -H-indol-20 -ylidene)-propenyl]indolium chloride (TIC) at pH 8.011.0 and the extraction of
ion associate coloured complex. This ion associate complex
(1:1) was detected and extracted with toluene and an absorption maximum at 566.2 nm against a blank reagent. The
calibration graph was linear from 0.9 to 11 lg mL1 of diclofenac and the LOD was 0.86 lg mL1 (Kormosh et al., 2008).
An extractive-spectrophotometric method for the preconcentration and determination of diclofenac was developed. In a
strong nitric acid medium, diclofenac produced a yellowish
compound in a water/tetrahydrofuran/peruorooctanoic acid
homogeneous phase that could be extracted into a sedimented
microdroplet. The concentration of the extracted coloured
compound in the microdroplet was determined by measuring
its absorbance at 376 nm. The maximum absorbance was
achieved in 1.5 and 7.0 mol L1 aqueous and methanolic solutions of nitric acid. The absorbance of diclofenac solutions in
water and methanol obeyed Beers law, over the range of 1.0
30 and 0.540 lg mL1, with molar absorptivities of 7.4 103
and 1.3 104 L mol1 cm1, respectively. The LOD achieved
with the proposed method was 0.03 ng mL1 (Ghiasvand
et al., 2008). A kinetic method based on a ligand-exchange
reaction for the determination of micro quantities of diclofenac sodium was described. The reaction was followed spectrophotometrically by monitoring the rate of appearance of the
cobalt diclofenac complex at 376 nm. The optimized conditions yielded a theoretical LOD of 1.29 lg mL1 based on
the 3Sb criterion (Mitic et al., 2007). An effective method for
the determination of sodium or potassium diclofenac is proposed in its pure form and in their pharmaceutical preparations. The method is based on the reaction between
diclofenac and tetrachloro-p-benzoquinone (p-chloranil), in
methanol medium. This reaction was accelerated by irradiating
of reactional mixture with microwave energy (1100 W) during
27 s, producing a charge transfer complex with a maximum
absorption at 535 nm. Beers law is obeyed in a concentration
range from of 1.25 104 to 2.00 103 mol L1 with a correlation coefcient of 0.9993 and molar absorptivity of
0.49 103 L mol1 cm1. The LOD was 1.35 105 mol L1
and the LOQ was 4.49 105 mol L1 (Ciapina et al., 2005).
A spectrophotometric method was proposed for determination
of sodium diclofenac in pharmaceutical preparations based on
its reaction with concentrated nitric acid (63% w/v). The reaction product is a yellowish compound with maximum absorbance at 380 nm. The corresponding calibration curve is
linear over the range of 1.030 lg L1, while the LOD is
0.46 lg L1 (Matin et al., 2005). A modied procedure for
the visible spectrophotometric determination of diclofenac, in
pharmaceutical preparations using as reagent an aqueous solution of copper(II), is proposed. A green colour complex is
formed between copper(II) and diclofenac with a maximum
light absorption at 680 nm. The optimal conditions were found
to be 5.3 (pH of the solution to be extracted), 50.0 mg mL1
(copper(II) acetate in 0.01 mol L1 acetic acid solution) and
three extractions with chloroform using a total volume of
5.0 mL. The intrinsic RSD of the proposed method was about
A.A. Gouda et al.

2.3% for sodium diclofenac and 2.7% for potassium
diclofenac. The linear correlation coefcient, r, was 0.9984
for sodium diclofenac salt and 0.9993 for potassium diclofenac
salt. The linear range goes from 1.0 to 25.0 mg mL1 in the
working solution. The LOD is 0.2 mg mL1 and the LOQ is
0.7 mg mL1 (De Souza and Tubino, 2005). A spectrophotometric method for the determination of diclofenac sodium in
pure form and in pharmaceutical formulations was developed.
The method is based on the oxidation of diclofenac sodium by
iron(II) in the presence of o-phenanthroline. The formation of
tris(o-phenanthroline) iron(II) complex (ferroin) upon the
reaction of diclofenac sodium with an iron(III)-o-phenanthroline mixture in acetate buffer solution of pH 4.4, respectively,
was investigated. The ferroin complex is measured at 510 nm
against a reagent blank prepared in the same manner. The
optimum experimental parameters for the colour production
are selected. Beers law is valid within a concentration range
of 1.032 lg mL1. For more accurate results, Ringbom optimum concentration ranges are 2.030 lg mL1. The molar
absorptivity is 1.15 104 L mol1 cm1, whereas Sandell sensitivity is 2.78 ng cm2. The method gave a mean percentage
recoveries 99.8 1.2% (El-Didamony and Amin, 2004).
Spectrophotometric determination of diclofenac sodium using
2,2-diphenyl-1-picrylhydrazyl (Salem, 2000) was investigated.
Simple spectrophotometric methods are described (Agrawal
and Shivramchandra, 1991) for the determination of diclofenac. In the rst method diclofenac reduces iron(III) to iron(II)
when heated in aqueous solution. The ferrous ions produced
react with 2,20 -bipyridine to form a complex having a maximum absorbance at 520 nm. The reaction obeys Beers law
for concentrations of 1080 lg mL1. In the second method,
diclofenac is treated with methylene blue in the presence of
phosphate buffer (pH 6.8) and the complex is extracted with
chloroform. The complex has a maximum absorbance at
640 nm and the graph of absorbance against concentration is
linear in the range 540 lg mL1. A multifactor optimization
technique was successfully applied to develop a new spectrophotometric method in which diclofenac sodium is analyzed
and determined as it is Fe(III) complex. The effect of simultaneously varying the pH, ionic strength and concentration of
colour reagents in the reaction mixture were studied. A fourvariable two-level factorial design was used to investigate the
signicance of each variable and interactions between them.
A response surface design was used to optimize complex formation and extraction. It was established that diclofenac reacts
with Fe(III) chloride, in the presence of ammonium thiocyanate, in the pH range 4.26.5, forming a red chloroform
extractable (2:1) complex with maximum absorbance at
481 nm. By applying the methods of Sommer and Job involving non-equimolar solutions the conditional stability constant
of the complex, at the optimum pH of 6.0 and an ionic strength
l = 0.19 mol L1, was found to be 106.4. Good agreement
with Beers law was found for diclofenac concentrations up
to 1.5715.7 mmol L1 (0.11.0 mg mL1). The nominal
percent recovery of diclofenac was 98.8% (n = 10). The lower
limit of sensitivity of the method was found to be
14.7 lg mL1 (Agatonovic-Kus trin et al., 1997). A colorimetric
method for the quantitative determination of diclofenac sodium in pure form and in pharmaceutical preparations was
developed. It was based on the interaction of the secondary
aromatic amine with p-dimethylaminocinnamaldehyde in acidied absolute methanol medium to form very stable red [kmax

at 538 nm] products. Beers law was obeyed over the range 10
80 lg mL1. The reactants were heated on a boiling water bath
for 6.0 min (El Sherif et al., 1997). A validated method has
been developed for estimation of diclofenac diethylammonium
in bulk and formulation. The present method utilizes the reaction of diclofenac diethylammonium with 1.0% w/v potassium
ferricyanide in presence of 0.5% w/v sodium hydroxide which
produces orange chromogen with maximum absorbance at
450 nm and obeys Beers law in the concentration range of
2.012 lg mL1. The chromogen is stable for more than
30 min (Validya and Parab, 1995). A spectrophotometric
method was described for the determination of diclofenac sodium in bulk samples and pharmaceutical preparations. The
method is based on the reaction of diclofenac sodium with pN,N-dimethylphenylenediamine in the presence of S2 O8 2 or
Cr(VI) whereby an intensely coloured product having maximum absorbance at 670 nm is developed. The reaction is sensitive enough to permit the determination of 2.024 lg mL1
(Sastry et al., 1989).
Two FI spectrophotometric methods were proposed for the
determination of diclofenac in bulk samples and pharmaceuticals. Both methods are based on the reaction of diclofenac
with potassium ferricyanide in a sodium hydroxide medium.
The absorbance of the orange products obtained is measured
at 455 nm. The corresponding calibration graphs are linear
over the range 0.2020 lg mL1, while the LOD were
0.05 lg mL1 (Garcia et al., 2001). A ow-through sensor
for the determination of diclofenac sodium was developed,
based on retention of the analyte on a Sephadex QAE A-25 anion-exchange resin packed in a ow-cell of 1.0 mm of optical
path length, and monitoring of its intrinsic absorbance by
UV-spectrophotometry at 281 nm. Diclofenac could be determined in the concentration ranges 2.040.0, 1.022.0 and
0.514.0 lg mL1 with RSD (%) ranging from 1.05 to 1.53
for sample volumes of 300, 600 and 1200 lL, respectively.
The proposed sensor was satisfactorily applied to the rapid
determination of diclofenac in commercial pharmaceutical
preparations and in semi-synthetic pharmaceuticals containing
diclofenac and paracetamol (Ortega-Barrales et al., 1999). A
FI spectrophotometric method for the determination of diclofenac sodium based on the formation of coloured compound
with Ce(IV)3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) in 3.0 102 mol L1 H2SO4 medium was
proposed. Using the peak height as a quantitative parameter
diclofenac was determined at 580 nm over the range 0.2
8.0 lg mL1. The method was successfully applied to the
determination of diclofenac in pharmaceuticals and urine samples (Garcia et al., 1998). Diclofenac sodium, famotidine and
ketorolac tromethamine were determined by FIA with spectrophotometric detection. The sample solution 5.050 lg mL1 of
diclofenac sodium, in methanol was injected into a ow system
containing 0.01% (w/v) of 2,4,dichloro-6-nitrophenol (DCNP)
in methanol. The colour produced due to the formation of a
charge transfer complex was measured with a spectrophotometric detector set at 450 nm. A sampling rate of 40 per hour
was achieved with high reproducibility of measurements
(RSD 6 1.6%) Kamath et al., 1994.
The spectrophotometric determination of trace amounts of
diclofenac was carried out by liquidliquid extraction using
acridine yellow with a ow system (Perez-Ruiz et al., 1997).
The determination of diclofenac sodium in the range of 3.0
80 lg mL1 was possible with a sampling frequency of 40 sam-
153
ples h1. The spectrouorometric determination of diclofenac
[2-(2,6-dichloroanilino)-phenylacetic acid] in pharmaceutical
tablets and ointments was described (Damiani et al., 1999).
It involves excitation at 287 nm of an acid solution (HCl
0.01 M) of the drug and measurement of the uorescence
intensity at 362 nm. The linear range is 0.25.0 lg mL1. No
interference is observed from the excipients or from other
drugs which accompany diclofenac in certain formulations
(paracetamol or cianocobalamine).
The next study focuses on the complex formed between
a-cyclodextrin (a-CD) and diclofenac in aqueous solution
and also on its potential analytical applications. It was corroborated that the uorescence emission band of diclofenac is
signicantly intensied in the presence of a-CD. From the
changes in the uorescence spectra, it was concluded that
a-CD forms a 1:1 inclusional complex with diclofenac and
its equilibrium constant was calculated to be 1.20(3)
103 mol L1. With the purpose of characterizing the inclusion
complex, the acidbase behaviour of diclofenac in both the
presence and absence of a-CD was spectrophotometrically
investigated. From the results obtained, it was inferred that
both the carboxyl and the secondary amino groups of the guest
molecule remain outside the cyclodextrin cavity. Further details on the complex structure were obtained by 1H NMR measurements and semiempirical calculations. In addition to the
analysis of the a-CD-diclofenac interaction, a new approach
for the quantication of diclofenac in the presence of a-CD
is described in the range 0.05.0 lg mL1 (Arancibia et al.,
2000). A spectrouorometric method for the microdetermination of diclofenac sodium has been developed through its reaction with cerium(IV) in an acidic solution and measurement of
the uorescence of the Ce(III) ions produced. Under the optimum experimental conditions for the oxidation reaction,
1.0 mol L1 H2SO4 with 90 min of heating time (100 C), the
range of application is 124.3600 ng mL1 and the limit of
detection is 72.7 ng mL1 (Castillo and Bruzzone, 2006). A
new method has been devised for the determination of diclofenac sodium in bulk and in pharmaceutical preparations using
Eu(III) ions as the uorescent probe. The technique was built
around the hypersensitive property of the transitions of the
uorescent probe ion, Eu(III), at 616 nm. This is normally a
forbidden transition, but the interaction with diclofenac sodium, which contains a carboxylic group, makes the transition
allowed and enhances the intensity of its uorescence emission.
The Eu(III) uorescence emission at 592 nm comes from a
non-hypersensitive transition and is not affected by ligation.
The intensity ratio, R, dened as I592/I616, was used as a measure of the percentage of bound probe ions. Diclofenac and
Eu(III) forms a (1:1) molar complex. The relative stability constant of the complex was found to be 105. A linear relationship
between bound Eu(III) and the concentration of diclofenac sodium was found for concentrations from 10 to 200 lg mL1,
with a recovery percentage of 100.22 2.27 (Carreira et al.,
1995).
3.3. Etodolac
The ofcial method of etodolac was potentiometric titration
method with tetrabutylammonium hydroxide (Pharmacopoeia,
2004).
Two spectrophotometric and spectrouorometric methods
were adopted for the analysis of the anti-inammatory drugs,
154
Table 2
A.A. Gouda et al.

Comparison between the spectrophotometric methods for determination of arylalkanoic acids.
Name of drug Method
kmax (nm)
Linear range
(lg mL1)
Ref.
Aceclofenac
273
276, 249 and 270
274.5
10100
2.025
2.020
up to 24
0.020
5.045
1.010
5.040
1040
1550
4.024
4.032
80160
1080
0.21.0
75200
20100
5.030
8.055
Nikam et al. (2007)

Jain et al. (2007)
Mahaparale et al. (2007)
Srinivasan et al. (2007)
Saravanan et al. (2006)
Dashora et al. (2006)
Mishra and Garg (2006)
Hasan et al. (2003)
UV methods
FolinCiocalteu
Orange G in acidic medium
Naphthol green in aqueous medium
Ferric nitrate in acidic medium
p-Dimethylaminocinnamaldehyde (PDAC)
2,2-Diphenyl-1-picrylhydrazyl (DPPH)
p-Dimethylaminobenzaldhyde reagent
(PDAB)/sulfuric acid/ferric chloride
Spectrouorimetric method
Diclofenac
UV methods
203
273.5
230
242
245
273
283
252
642.6
481
633.6
470
665.5
520
545.5
kem = 355
kex = 250
277, 295 (isobestic

point), and 320
277
277, 295 and 320.4
230320
1.050
1245
1445
1050 lmol L1
276
260 and 265
276
566.2
0.911
3,3-Trimethyl-5-thiocyanato-2[3-(10 ,30 ,30 -trimethyl-30 -H-indol-20 -ylidene)-propenyl]indolium chloride (TIC)

Nitric acid in aqueous media
376
Nitric acid in methanol media
Kinetic method
376
p-Chloranil, in methanol medium
535
Concentrated nitric acid (63% w/v)
Copper (II)
Iron(II)/o-phenanthroline
2,2-Diphenyl-1-picrylhydrazyl
Fe3+/2,20 -bipyridine
Fe(III)/ammonium thiocyanate pH range (4.26.5)
p-Dimethyl-aminocinnamaldhyde
potassium ferricyanide/NaOH
p-N,N-Dimethylphenylenediamine/S2 O8 2 or Cr(VI)
Flow injection with potassium
ferricyanide/sodium hydroxide
Flow-through sensor
Flow-injection with Ce(IV)(MBTH)/H2SO4
Flow injection with 2,4,dichloro6-nitrophenol (DCNP) in ethanol
Spectrouorimetric methods with -cyclodextrin
with cerium(IV) in an acidic solution
with Eu3+ ions
2.08.0
380
680
510
520
481
538
450
670
455
281
580
450
kem = 592
kex = 616
1.030
0.540
1.25 1042
103 mol L1
1.030
1.025
1.032
1080
El-Saharty et al. (2002)

Singhvi and Goyal (2007)
Goyal and Singhvi (2006)
Mishra and Garg (2006)
Zawilla et al. (2002)
Salem (2000)
El Kousy (1999)
El Kousy (1999)
Sanjay et al. (2006)
Ghasemi et al. (2005a)

Ghasemi et al. (2005b)
Sena et al. (2004)
Bucci et al. (1998)
Karamancheva et al. (1998)
Bhatia et al. (1996)
Kormosh et al. (2008)
Ghiasvet al. (2008)

Mitic et al. (2007)
Ciapina et al. (2005)
1080
2.012
2.024
0.220
Matin et al. (2005)

De Souza and Tubino (2005)
El-Didamony and Amin (2004)
Salem (2000)
Agrawal and Shivramchandra (1991)
Agatonovic-Kus trin et al. (1997)
El Sherif et al. (1997)
Validya and Parab (1995)
Sastry et al. (1989)
Garcia et al. (2001)
2.040
0.208.0
5.050
Ortega-Barrales et al. (1999)

Kamath et al. (1994)
0.05.0
0.12430.600
10200
Arancibia et al. (2000)

Castillo and Bruzzone (2006)
Carreira et al. (1995)

Table 2
155
(continued)
Name of drug
Method
kmax (nm)
Linear range
(lg mL1)
Ref.
Etodolac
p-Dimethylaminobenzaldhyde reagent
(PDAB)/sulfuric acid/ferric chloride
Fe(III)/o-phenanthroline (o-phen)
Fe(III)3+/bipyridyl (Bipy)
Fe(III)/ferricyanide
Fe(III)/2,20 -bipyridyl
TCNE
DDQ
p-CHL
Copper(II) acetate
Iron(III) chloride
591.5
1080
El Kousy (1999)
510
520
725
500
0.58
1.010
2.018
0.525
Gouda and Hassan (2008)
684
385
k = 345 kex = 235
2.09.0
0.52.0 mg mL1
0.0960.640
Amer et al. (2005)

El Kousy (1999)
684
450
1060
10120
Shingbal and Naik (1997)

Kamath et al. (1994)
kex = 255
kem = 365
0.10.8
Eid et al. (2007)
Ketorolac
(MBTH)/Fe(III)
Flow injection analysis (FIA): 2,4,dichloro6-nitrophenol (DCNP) in methanol
Spectrouorometry in cerium(IV)/H2SO4
etodolac and aceclofenac. The rst method is based on the formation of coloured complexes between the drugs and pdimethylaminobenzaldehyde reagent (PDAB) in the presence
of sulfuric acid and ferric chloride. Measurement of the absorbance was carried out at 591.5 nm for etodolac. Regression
analysis of Beers plots showed good correlation in the concentration ranges 1080 lg mL1. The second was the spectrouorometric method in which samples of etodolac in ethanol
showed native uorescence at a k = 345 nm when excitation
was at 235 nm. The calibration graph was rectilinear from 96
to 640 ng mL1. The proposed methods were applied successfully for the determination of the two drugs in bulk powder
with a mean accuracy of 100.48 0.85 in the PDAB method
and of 99.88 0.45 in the spectrouorometric method (El
Kousy, 1999).
Gouda and Hassan have described (Gouda and Hassan,
2008) three spectrophotometric methods (AC) for the determination of etodolac in pure form and in pharmaceutical formulations. The rst and second methods, A and B, are based
on the oxidation of the studied drugs by Fe(III) in the presence
of o-phenanthroline (o-phen) or bipyridyl (Bipy). The formation of tris-complex upon reactions with Fe(II)-o-phen and/
or Fe(III)-Bipy mixture in an acetate buffer solution of the
optimum pH-values was demonstrated at 510 and 520 nm with
o-phen and Bipy. The third method C, is based on the reduction of iron(III) by etodolac in acid medium and subsequent
interaction of iron(II) with ferricyanide to form prussian blue
and the product exhibits absorption maximum at 725 nm. The
concentration ranges are from 0.5 to 8.0, 1.0 to 10 and 2.0 to
18 lg mL1 for methods A, B and C, respectively.
A spectrophotometric method for the determination of
etodolac was described. This method based on the etodolac
can reduce Fe(III) to Fe(II) in the presence of 2,20 -bipyridyl
(Bipy) and pH 3.56.0 acetate buffer medium. The Fe(II) can
react with Bipy to form a Fe(II)Bipy coloured complex.
The maximum absorbance of the coloured complex is at
500 nm. Beers law is obeyed in the range of 0.525 lg mL1
for etodolac. The method was applied to the determination
of etodolac in tablets without any interference from common
Hu et al. (2008)
Duymus et al. (2006)
excipients. The RSD was 0.82% with recoveries 97102%

(Hu et al., 2008).
Spectrophotometric method for the determination of etodolac was described. This method is based on the oxidation of
the studied drugs by Fe3+ in the presence of o-phenanthroline
(o-phen) medium. The formation of tris-complex upon reactions with Fe3+o-phen in an acetate buffer solution of the
optimum pH-values was demonstrated at 510 nm with o-phen.
The concentration ranges are from 0.5 to 20 lg/mL for this
method. The relative standard deviations were 60.76% with
recoveries 99101% (Ye et al., 2009).
Charge transfer (CT) complexes of etodolac, which is electron donor with some p-acceptors, such as tetracyanoethylene
(TCNE), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), pchloranil (p-CHL), have been investigated spectrophotometrically in chloroform at 21 C. The coloured products are measured spectrophotometrically at different wavelength
depending on the electronic transition between donors and
acceptors. Beers law is obeyed and colours were produced in
non-aqueous media. All complexes were stable at least 2.0 h
except for etodolac with DDQ stable for 5.0 min. The equilibrium constants of the CT complexes were determined by the
BenesiHildebrand equation. The thermodynamic parameters
DH, DS, DG were calculated by Vant Hoff equation. Stoichiometry of the complexes formed between donors and acceptors
were dened by the Jobs method of the continuous variation
and found in 1:1 complexation with donor and acceptor at the
maximum absorption bands in all cases (Duymus et al., 2006).
A method depends on complexation of etodolac with copper(II) acetate and iron(III) chloride followed by extraction
of complexes with dichloromethane and then measuring the
extracted complexes spectrophotometrically at 684 and
385 nm in case of Cu(II) or Fe(III), respectively, was developed. Different factors affecting the reaction, such as pH, reagent concentration, and time were studied. By use of Jobs
method of continuous variation, the molar ratio method,
and elemental analysis, the stoichiometry of the reaction was
found to be in the ratio of 1:2 and 1:3, metal: drug in the case
of Cu(II) and Fe(III), respectively. The method obeys Beers
156
law in a concentration range of 2.09.0 and 0.52.0 mg mL1
in case of Cu(II) and Fe(III), respectively. The stability of
the complexes formed was also studied, and the reaction products were isolated for further investigation. The complexes
have apparent molar absorptivity of about 32.14 0.97 and
168.32 1.12 for Cu(II) and Fe(III), respectively (Amer
et al., 2005).
3.4. Ketorolac
The ofcial method of ketorolac was potentiometric titration
method with tetrabutylammonium hydroxide (Pharmacopoeia,
2004).
A spectrophotometric method has been developed for the
estimation of ketorolac tromethamine and its dosage forms,
based on its reaction with 3-methyl-2-benzothiazolinone
hydrazone hydrochloride (MBTH) in presence of Fe(III) ion
yielding a green coloured chromogen with absorption maxima
at 684 nm. Beers law is obeyed in the concentration range of
1060 lg mL1 (Shingbal and Naik, 1997).
Ketorolac tromethamine was determined by FIA with
spectrophotometric detection. The sample solution 10120
lg mL1 in methanol was injected into a ow system containing
0.01% (w/v) of 2,4,dichloro-6-nitrophenol (DCNP) in methanol. The colour produced due to the formation of a charge transfer complex was measured with a spectrophotometric detector
set at 450 nm (Kamath et al., 1994).
A uorometric method for determination of ketorolac tromethamine was studied. The method depends on oxidation of
the drug with cerium(IV) and subsequent monitoring of the
uorescence of the induced cerium(III) at kem 365 nm after
excitation at 255 nm. Different variables affecting the reaction
conditions, such as the concentrations of cerium(IV), sulfuric
acid concentration, reaction time, and temperature, were carefully studied and optimized. Under the optimum conditions, a
linear relationship was found between the relative uorescence
intensity and the concentration of the investigated drug in the
range of 0.10.8 lg mL1 (Eid et al., 2007).
Table 2 shows comparison between the published spectrophotometric and spectrouorometric methods for arylalkanoic
acids.
determination of N-arylanthranilic acids derivatives (fenamic
acids)
4.1. Mefenamic acid
The ofcial method of mefenamic acid was potentiometric
titration method with sodium hydroxide (Pharmacopoeia,
2004).
Two spectrophotometric methods for simultaneous estimation of two-component drug mixture of ethamsylate and mefenamic acid in combined tablet dosage form have been
developed. The rst developed method involves formation
and solving of the simultaneous equation using 287.6 and
313.2 nm as two wavelengths. The second developed method
is based on two wavelengths selected for estimation of
mefenamic acid which were 304.8 and 320.4 nm (Goyal and
Singhvi, 2008). The spectrophotometric methods for the determination of mefenamic acid and ethamsylate in pharmaceutical formulations have been developed. The methods are
A.A. Gouda et al.

based on the additivity of absorbances and the determination
of graphical absorbance ratio at two selected wavelengths,
one being the isoabsorptive point for the two drugs (301 nm)
and the other being the absorption maximum of mefenamic
acid (336 nm). The BeerLamberts law is obeyed for
mefenamic acid in the concentration range 4.028 lg mL1
(Garg et al., 2007). Two new, simple, accurate and economical
spectrophotometric methods have been developed for simultaneous estimation of drotaverine hydrochloride and mefenamic
acid in two-component tablet formulation. The methods employed are, rst derivative spectrophotometry, using zero
crossing technique and multicomponent analysis. Both the
drugs obey the Beers law in the concentration range of
432 lg mL1. For quantitative estimation, absorbances were
measured at kmax of both the drugs viz. 279 and 308 nm for
MA and DH, respectively. The assay values for tablets, were
in the range of 99.1599.30% for MA (Dahivelkar et al.,
2007). A spectrophotometric method in the UV range has been
developed for the simultaneous determination of mefenamic
acid and paracetamol in bulk and in dosage forms. Mefenamic
acid shows three absorbance maxima at 219, 284 and 336 nm
in 0.1 mol L1 sodium hydroxide (Dhake et al., 2001). A
simultaneous spectrophotometric procedure for the determination of mefenamic acid and paracetamol in two component
tablet formulations has been developed. The method is based
on the two-wavelength method of calculations. The difference
in absorbance at 217 and 285 nm was used for determination
of mefenamic acid (Gangwal and Sharma, 1996).
In the Vierordts spectrophotometric method, the drugs
were determined by using the absorptivity values of mefenamic
acid at selected wavelengths, viz., 216.8 nm, respectively. In Qanalysis method, isoabsorptive point was found to be at
224.6 nm. The drug obeys Beers law in concentration range
of 418 lg/mL (Kumar et al., 2009).
A simple visible spectrophotometric method is described
for the determination of mefenamic acid in bulk sample and
pharmaceutical preparations. The method is based on the
reaction of mefenamic acid with p-N,N-dimethylphenylenediamine in the presence of S2 O8 2 or Cr(VI) whereby an intensely coloured product having maximum absorbance at 740 nm
is developed. The reaction is sensitive enough to permit the
determination of 0.254.0 lg mL1 (Sastry et al., 1989). Spectrophotometric methods for the determination of mefenamic
acid, based on the formation of a coloured species with
MBTH on oxidation with Ce(IV) or Fe(III), are described
(Sastry and Rao, 1989). A method for the quantitative determination of mefenamic acid in pharmaceutical preparations
was proposed. The method is based on the formation of blue
complexes with FolinCiocalteu reagent (Sastry and Rao,
1988). A spectrophotometric method was developed for the
determination of mefenamic acid in the pure form and in
pharmaceutical dosage forms. The method depends on their
complexation with copper(II) ammonium sulphate. The complex was extracted with chloroform and treated with diethyldithiocarbamate solution, where upon another copper(II)
complex (kmax 430 nm) was formed. Beers law is followed
over the concentration range 6.048 lg mL1 for mefenamic
acid (Khier et al., 1987). Spectrophotometric determination
of ufenamic acid, mefenamic acid, allopurinol and indomethacin using N-bromosuccinimide was studied (Hassib
et al., 1986). Spectrophotometric determination of mefenamic
acid with sodium cobaltinitrite was investigated (Sastry et al.,

1985). Mefenamic and ufenamic acids could be determined
colorimetrically after extraction as ion-pairs with methylene
blue (Issa et al., 1985). Extractive spectrophotometric determination of ibuprofen, ketoprofen, piroxicam, diclofenac
sodium, mefenamic acid and enfenamic acid with methylene
violet was illustrated (Sastry et al., 1989).
Low-cost spectrophotometric method for the determination
of mefenamic acid in its pure form and pharmaceutical preparations was developed. The method is based on the chargetransfer complexation between mefenamic acid as an n-electron
donor and chloranil as a p-acceptor to form a violet chromogen measured at 540 nm. Under the optimum conditions, a
linear relationship with a good correlation coefcient (0.9996)
was found between the absorbance and concentration of the
studied drug in the range of 1060 lg mL1. The LOD was
2.16 lg mL1 and LOQ was 7.15 lg mL1 (Raza, 2008). Mefenamic acid reacts with p-dimethylaminobenzaldehyde to give a
bluish-green complex in acidic media after heating for 90 s at
90 C, having maximum absorbance at 597.5 nm. The reaction
is selective for mefenamic acid with 2.0 lg mL1 as visual limit
of quantitation and provides a basis for a new spectrophotometric determination. The reaction obeys Beers law from 2.0
to 25 lg mL1 of mefenamic acid and the RSD is 0.50%
(Aman et al., 2005). A colorimetric method for the quantitative determination of mefenamic acid in pure form and in
pharmaceutical preparations was developed. It was based on
the interaction of the secondary aromatic amine with p-dimethylaminocinnamaldehyde in acidied absolute methanol
medium to form very stable blue product [kmax at 665 nm].
Beers law was obeyed over the ranges 1.08.0 lg mL1. The
reactants were heated on a boiling water bath for 5.0 min. Optimization of the different experimental conditions were studied. The mean percentage recoveries was found to be
100.73 0.44%. The method was applied successfully for
the determination of some pharmaceutical formulations. (El
Sherif et al., 1997). Three simple, rapid and accurate spectrophotometric methods were developed for the determination
of mefenamic acid. The rst method (method I) is based on
the reaction of mefenamic acid as N-donor with p-chloranilic
acid as a p-acceptor. A red colour product shows peak at
520 nm and its absorbance is linear with concentration over
the range 10300 lg/mL with correlation coefcient (n = 12)
of 0.9997. The second method (method II) involves oxidation
of mefenamic acid with N-bromosuccinimide. A yellow colour
product shows peak at 362 nm and its absorbance is linear
with concentration over the range 570 lg mL1 with correlation coefcient (n = 8) of 0.9999. The third method (method
III) is based on the formation of an oxidative coupling product
by the reaction of mefenamic acid with 3-methylbenzo-thiazolin-2-one hydrazone as a chromogenic reagent in presence of
ferric chloride solution. A green colour product shows peak
at 602 nm and its absorbance is linear with concentration over
the range 16 lg/mL with correlation coefcient (n = 6) of
0.9999 (Alarfaj et al., 2009).
FI spectrophotometric method was proposed for the determination of mefenamic acid in bulk sample and pharmaceuticals. The method is based on the reaction of mefenamic acid
with potassium ferricyanide in a sodium hydroxide medium.
The absorbance of the orange product obtained is measured
at 465 nm. The corresponding calibration graphs are linear
over the range 1.0100 lg mL1 for mefenamic acid, while
the limits of detection were 0.18 lg mL1 (Garcia et al., 2001).
157
A spectrouorometric method was developed for determination of mefenamic acid in pharmaceutical preparation and
human urine. The procedure is based on the oxidation of
mefenamic acid with cerium(IV) to produce cerium(III), and
its uorescence was monitored at 354 nm after excitation at
255 nm. Under the experimental conditions used, the calibration graphs were linear over the range 0.031.5 lg mL1. The
limit of detection was 0.009 lg mL1 and the relative standard deviation for ve replicate determinations of mefenamic
acid at 1.0 lg mL1 concentration level was 1.72% (Tabrizi,
2006). Terbium sensitized uorescence was used to develop
a sensitive and simple spectrouorometric method for the
determination of the anthranilic acid derivatives (mefenamic
acid). The method makes use of radiative energy transfer
from anthranilates to terbium ions in alkaline methanolic
solutions. Optimum conditions for the formation of the
anthranilateTb(III) complexes were investigated. Under optimized conditions, the LOD are 1.4 108 mol L1. The range
of application is 2.5 1085.0 105 mol L1. The method
was successfully applied to the determination of mefenamic
acid in serum after extraction of the samples with ethyl
acetate, evaporation of the organic layer under a stream of
nitrogen at 40 C and reconstitution of the residue with
alkaline methanolic terbium solution prior to instrumental
measurement. The mean recoveries from serum samples
spiked with mefenamic acid (3.0 106, 9.0 106 and
3.0 105 mol L1) were 101 5.0 (Ioannou et al., 1998).
Second-order advantage of excitationemission uorescence
measurements was applied to the simultaneous determination
of paracetamol (PC) and mefenamic acid (MF) in urine
samples. Two drugs were quantied by multivariate curve
resolution coupled to alternative least squares (MCR-ALS)
in micellar media of sodium dodecyl sulphate (SDS). Experimental conditions including pH and SDS concentration
were optimized. Under the optimum conditions, pH 2.0 and
0.05 mol L1 of SDS, mefenamic acid was determined in
concentration range 0.805.00 lg mL1, in urine samples
(Madrakian et al., 2009).
4.2. Flufenamic acid
The ofcial method of ufenamic acid was potentiometric
2004).
A spectrophotometric method was developed for the determination of ufenamic in the pure form and in pharmaceutical
dosage forms. The method depends on their complexation with
copper(II) ammonium sulphate. The complex is extracted with
chloroform and treated with diethyldithiocarbamate solution,
whereupon another copper(II) complex (kmax 430 nm) is
formed. Beers law is followed over the concentration ranges
6.060 lg mL1 for ufenamic acid (Khier et al., 1987).
Spectrouorometric method for determination of ufenamic acid in bulk powder and capsule dosage forms was presented. The methods are based on the cyclization reaction of
ufenamic acid with concentrated sulfuric acid to produce
the corresponding acridone derivative and measurement of
the uorescence intensity at 450 nm (kex = 400 nm) and
peak-to-peak measurements of the rst- (1D) and secondderivative (2D) curves, respectively. Beers law is obeyed
over the concentration ranges of 2.020 ng mL1 (Sabry and
Mahgoub, 1999).
158
A.A. Gouda et al.
4.3. Enfenamic acid
4.4. Tolfenamic acid
The ofcial method of enfenamic acid was potentiometric

2004).
Spectrophotometric method for the quantitative determination of enfenamic acid and naproxen (after demethylation)
based on the formation of a coloured oxidative coupling product with 2,6-dichloro-p-benzoquinone-4-chlorimine (Gibbs reagent) in phosphate buffer (pH 7.0) was developed. The
reaction is sensitive to permit the determination of
0.25 lg mL1 of enfenamic (Sastry et al., 1988).
A simple visible spectrophotometric method was described
for the determination of enfenamic acid in bulk samples and
pharmaceutical preparations. The method is based on the reaction of enfenamic acid with p-N,N-dimethylphenylenediamine
in the presence of S2 O8 2 or Cr(VI) whereby an intensely coloured product having maximum absorbance at 720 nm is
developed. The reaction is sensitive enough to permit the determination of 0.1252.0 lg mL1 (Sastry et al., 1989).
The ofcial method of tolfenamic acid was potentiometric

2004).
Terbium sensitized uorescence was used to develop a sensitive and simple spectrouorimetric method for the determination of the anthranilic acid derivative (tolfenamic acid).
The method makes use of radiative energy transfer from anthranilates to terbium ions in alkaline methanolic solutions.
Optimum conditions for the formation of the anthranilate
Tb(III) complexes were investigated. Under optimized conditions, the LOD was 9.0 109 mol L1. The range of application is 2.5 1085.0 105 mol L1. The method was
successfully applied to the determination of tolfenamic acid
in serum after extraction of the samples with ethyl acetate, evaporation of the organic layer under a stream of nitrogen at
40 C and reconstitution of the residue with alkaline methanolic terbium solution prior to instrumental measurement. The
mean recoveries from serum samples spiked with tolfenamic
Table 3
Comparison between the spectrophotometric methods for determination of N-arylanthranilic acids (fenamic acids).
Name of drug
Method
kmax (nm)
Linear range
(lg mL1)
Ref.
Mefenamic acid
UV methods
336 nm
219, 284 and 336
217 and 285
740
4.028
0.254.0
Garg et al. (2007)

Dhake et al. (2001)
Gangwal and Sharma (1996)
6.048
Sastry and Rao (1989)

Sastry and Rao (1988)
Khier et al. (1987)
p-N,N-Dimethylphenylenediamine/S2 O8 2 or
Cr(VI)
MBTH/Ce(IV) or Fe(III)
FolinCiocalteu
Copper(II) ammine sulphate/
diethyldithiocarbamate
N-Bromosuccinimide
Sodium cobaltinitrite
Methylene blue
Methylene violet
Chloranil
p-Dimethylaminobenzaldehyde
p-Dimethylaminocinnamaldehyde
p-Chloranilic acid
N-Bromosuccinimide
3-Methylbenzo-thiazolin-2-one hydrazone
as + ferric chloride
Flow injection with potassium ferricyanide/
sodium hydroxide
Spectrouorometric methods with cerium(IV)
in an acidic solution
430
Hassib et al. (1986)

Issa et al. (1985)
Raza (2008)
Aman et al. (2005)
El Sherif et al. (1997)
Alarfaj et al. (2009)
540
597.5
665
520
362
602
1060
2.025
1.08.0
10300
570
16
465
1.0100
kem = 354
0.031.5
Tabrizi (2006)
2.5 1085.0
105 mol L1
Ioannou et al. (1998)
430
6.060
Sabry and Mahgoub (1999)
kem = 450
2.020 ng mL1
Khier et al. (1987)
0.1252.0

kex = 255
with terbium Tb(III)
Flufenamic acid
Copper(II) ammine sulphate/

diethyldithiocarbamate
Spectrouorometry with concentrated sulfuric
acid
kex = 400
Enfenamic acid
Tolfenamic acid
2,6-Dichloro-p-benzoquinone-4-chlorimine
p-N,N-Dimethylphenylenediamine/S2 O8 2
Spectrouorometry with terbium Tb(III)
720
2.5 1085.0
105 mol L1
Ioannou et al. (1998)

acid (3.1 106, 12.5 106 and 2.5 105 mol L1) were
98 7.0% (Ioannou et al., 1998).
Table 3 shows comparison between the published spectrophotometric and spectrouorometric methods for fenamic
acids.
determination of arylpropionic acids (profens)
5.1. Ibuprofen
The ofcial method of ibuprofen was potentiometric titration
The simultaneous determination of paracetamol, ibuprofen
and caffeine in pharmaceuticals by chemometric approaches
using UV spectrophotometry has been reported as a simple
alternative to using separate models for each component. Spectra of paracetamol, ibuprofen and caffeine were recorded at
several concentrations within their linear ranges and were used
to compute the calibration mixture between wavelengths 200
and 400 nm at an interval of 1.0 nm in methanol: 0.1 mol L1
HCl (3:1). Partial least squares regression (PLS), genetic algorithm coupled with PLS (GA-PLS), and principal componentarticial neural network were used for chemometric analysis of
data and the parameters of the chemometric procedures were
optimized. The analytical performances of these chemometric
methods were characterized by relative prediction errors and
recoveries (%) and were compared with each other (Khoshayand et al., 2008). A spectrophotometric method for the simultaneous and separate estimation of ibuprofen and paracetamol
in binary tablet formulation has been developed. This method
is based on the estimation of one drug in presence of another
drug by absorbance difference method. The ibuprofen and
paracetamol solution were scanned over a range of 200
600 nm. In this method, two wavelengths 220 and 231 nm were
chosen for ibuprofen and at these wavelengths the absorbance
difference was almost zero while there was considerable absorbance difference in case of paracetamol, similarly. The amount
of ibuprofen was directly proportional to the absorbance difference between 241 and 255 mm (Omry et al., 2007). A simple
method was proposed for determination of paracetamol and
ibuprofen in tablets, based on UV measurements and partial
least squares. The procedure was performed at pH 10.5, in
the concentration range 2.412.0 lg mL1 (ibuprofen). The
model was able to predict paracetamol and ibuprofen in synthetic mixtures with root mean squares errors of prediction
of 0.17 lg mL1 (Sena et al., 2007). Spectrophotometric methods were described for the simultaneous determination of
pseudoephedrine hydrochloride and ibuprofen in their combination. The obtained data were evaluated by using ve different methods. In the rst method, ratio spectra derivative
spectrophotometry, analytical signals were measured at the
wavelengths corresponding to either maximums and minimums for both drugs in the rst derivative spectra of the ratio
spectra obtained by using each other spectra as divisor in their
solution in 0.1 mol L1 HCl. In the other four methods using
chemometric techniques, classical least-squares, inverse leastsquares, principal component regression and partial leastsquares (PLS), the concentration data matrix were prepared
by using the synthetic mixtures containing these drugs in methanol: 0.1 mol L1 HCl (3:1). The absorbance data matrix corresponding to the concentration data matrix was obtained by
159
the measurements of absorbance in the range 240285 nm in
the intervals with Dk = 2.5 nm at 18 wavelengths in their
zero-order spectra, then, calibration or regression was obtained by using the absorbance data matrix and concentration
data matrix for the prediction of the unknown concentrations
of pseudoephedrine hydrochloride and ibuprofen in their mixture. The procedures did not require any separation step. The
linear range was found to be 3001300 lg mL1 in all ve
methods (Palabiyik et al., 2004). Two procedures for simultaneous estimation of ibuprofen and methocarbamol in two
component tablet formulation have been developed. Solutions
were prepared in 0.1 mol L1 sodium hydroxide using all glass
double distilled water. Ibuprofen has an absorbance maximum
at 222 nm (Manikandan et al., 2001). The second-derivative
spectrophotometric method for the simultaneous determination of pseudoephedrine in the combinations with ibuprofen
was described. The second-derivative order of the spectra in
ethanol with the wavelength modulation was used. For the
quantitative assay for all of the investigated substances in the
laboratory mixture or in respective pharmaceutical dosage
forms, the zero-crossing technique was applied (Ivanovic
et al., 2000). A spectrophotometric method requiring no prior
separation has been developed. The method employs rst
derivative ultraviolet spectrophotometry for the simultaneous
estimation of ibuprofen and dextropropoxyphene hydrochloride. In aqueous methanol (10% v/v), ibuprofen has a maximum at 256 nm. In derivative spectroscopy, estimation of
ibuprofen was carded out in rst order with N = 6 at
232 nm (Sachan and Trivedi, 1998). Reproducible method
for estimation of ibuprofen and pseudoephedrine hydrochloride in combined dosage form has been developed. The method
involves two-wavelength calculation. The two wavelengths selected for estimation of ibuprofen are 264.0 and 254.5 nm
(Singhvi and Chaturvedi, 1998a). Two methods for simultaneous estimation of ibuprofen and pseudoephedrine hydrochloride in combined dosage form have been developed.
First developed method employs formation and solving of
simultaneous equations using 263.8 and 257.6 nm as two wavelengths for formation of equations. Second method involves
rst derivative ultraviolet spectroscopy. Two wavelengths selected for this method are 265 and 257 nm (Singhvi and Chaturvedi, 1998b).
A new extractive spectrophotometric method for the determination of ibuprofen was developed. The method involves the
formation of coloured electron donoracceptor complex between ibuprofen and safranine in the aqueous phase extractable into chloroform, which is measured at kmax 520 nm.
This method is extended to pharmaceutical dosage forms
(Babu, 1998). Kinetic spectrophotometric method for the
determination of ibuprofen in pharmaceutical formulations.
Ibuprofen was determined in an acidic ethanolic medium by
monitoring the rate of appearance of 1-nitroso-2-naphthol,
resulting from the displacement by ibuprofen of Co(III) from
the tris(1-nitroso-2-naptholato)cobalt(III) complex. The optimum operating conditions regarding reagent concentrations
and temperature were established. The tangent method was
adopted for constructing the calibration curve, which was
found to be linear over the concentration range 0.211.44
and 1.442.06 lg mL1 (Mitic et al., 2008).
A spectrophotometric method was presented for the determination of ibuprofen by batch and ow injection analysis
methods. The method is based on ibuprofen competitive
160
complexation reaction with phenolphthalein-b-cyclodextrin
(PHP-b-CD) inclusion complex. The increase in the absorbance
of the solution at 554 nm by the addition of ibuprofen was measured. Ibuprofen can be determined in the range 8.0 106
3.2 104 and 2.0 1055.0 103 mol L1 by batch and
ow methods, respectively. The LOD and LOQ were 6.19
106 and 2.06 105 mol L1 for batch and 1.77 105 and
5.92 105 mol L1 for ow method, respectively. The sampling rate in ow injection analysis method was 120 5.0
samples h1. The method was applied to the determination of
pharmaceutical formulations (Afkhami et al., 2007).
The inclusion complexation of ibuprofen with b-CD has
been examined by means of spectrouorometry at both acid
and alkaline pH. The results suggest that stable 1:1 complexes
are formed in both media. The analysis of the pKa values for
ibuprofen in both the absence and presence of b-CD (4.12
and 4.66, respectively) suggests that in the inclusion complex
the carboxylic group is located outside the a-cyclodextrin (aCD) but interacting with it. Further structural characterization
of the complex was carried out by means of AM1 semiempiral
calculations. Based on the obtained results, a spectrouorometric method for the determination of ibuprofen in the presence of b-CD at 10 C was developed in the range of 4.7
58 lg mL1. Better LOD (1.6 lg mL1) and LOQ
(4.7 lg mL1) were obtained in this latter case with respect
to those obtained in the absence of b-CD. The method was satisfactorily applied to the quantication of ibuprofen in pharmaceutical preparations. A novel spectrouorometric
determination of ibuprofen in the presence of b-CD was also
developed for serum samples at concentration levels between
5.0 and 70 lg mL1 (Hergert and Escandar, 2003).
The characteristics of hostguest complexation between bcyclodextrin (b-CD) and two forms of ibuprofen (protonated
and deprotonated) were investigated by uorescence spectrometry. Stoichiometry for both complexes were established to be
1:1 and their association constants at different temperatures
were calculated by applying a non-linear regression method
to the change in the uorescence of ibuprofen that was brought
about by the presence of b-CD. The thermodynamic parameters (DH, DS and DG) associated with the inclusion process
were also determined. Based on the obtained results, a sensitive
spectrouorometric method for the determination of ibuprofen was developed with a linear range of 0.12.0 lg mL1 with
LOD of 0.03 lg mL1 (Manzoori and Amjadi, 2003).
The spectrouorometric determination of ibuprofen in
pharmaceutical tablets, creams and syrup is described. It involves excitation at 263 nm and emission at 288 nm. The linear
range is 2.073 lg mL1 (Damiani et al., 2001).
Luminescence properties of the complexes of terbium(III)
with ibuprofen and orthofen were studied. It was demonstrated that in the presence of organic bases (2,20 -dipyridyl
and o-phenanthroline) mixed-ligand complexes are formed
and the luminescence intensity of terbium(III) increases by a
factor of up to 250. The LOD are 2.0 and 0.05 lg mL1,
respectively (Teslyuk et al., 2007).
5.2. Ketoprofen
The ofcial method of ketoprofen was potentiometric titration
A binary mixture of hyoscine butylbromide and ketoprofen
was determined by four different methods. The rst involved
A.A. Gouda et al.

determination of ketoprofen was by using the ratio-spectra
rst-derivative spectrophotometric technique at 234 nm over
the concentration ranges of 5.045 lg mL1. The second method utilized second-derivative spectrophotometry over the concentration ranges of 5.035 lg mL1 with mean accuracies
99.55 1.15%, respectively. The third method was based on
the resolution of the two components by bivariate calibration
depending on a simple and rapid mathematical algorithm and
quantitative evaluation of the absorbance at 254 nm over concentration ranges of 5.035 lg mL1; mean accuracies of
100.19 1.07% were obtained for ketoprofen. The fourth
method was reversed-phase liquid chromatography using
0.05 mol L1 ammonium dihydrogen phosphateacetonitrile
methanol (20 + 30 + 6, v/v) as the mobile phase with ultraviolet detection at 220 nm over concentration ranges of 1.090
and 5.070 lg mL1; mean accuracies were 99.92 1.02%
and 99.61 0.98%, for hyoscine butylbromide and ketoprofen, respectively (El-Saharty et al., 2007). Partial least-squares
calibration was used for the simultaneous UV spectrophotometric determination of the active principle (ketoprofen) and
preservative (parabens) in a pharmaceutical preparation commercially available in gel form. Calibration mixtures were prepared by mixing pure solutions of the analytes (Blanco et al.,
1997). A second order derivative spectrophotometric method
was developed for the permeative determination of ketoprofen
in vitro. The method can avoid the disturbance of skin tissue
(Hu et al., 1997). The mean recovery of ketoprofen is
99.00 1.51%.
A spectrophotometric determination of ketoprofen based
upon oxime formation followed by charge transfer complexation with o-chloranil has been developed. Different variables
affecting the complexation process have been studied. Beers
law is obeyed in the concentration range 1080 lg mL1 (ElSadek et al., 1993).
5.3. Flurbiprofen
The ofcial method of urbiprofen was potentiometric titration method with sodium hydroxide (Pharmacopoeia, 2004).
A UV spectrophotometric method for quantitative estimation of urbiprofen in pure form and in pharmaceutical dosage
forms was developed. The linear regression equations obtained
by least square regression method were Abs = 7.5906 102
concentration (lg mL1) 4.6210 102 for the UV method.
The detection limit as per the error propagation theory was
found to be 0.34 lg mL1 for UV method (Sajeev et al., 2002).
5.4. Naproxen
The ofcial method of naproxen was potentiometric titration
A second-derivative spectrophotometric method for the
determination of naproxen in the absence or presence of its 6desmethyl metabolite in human plasma is described. The method consists of direct extraction of the non-ionized form of the
drug with pure diethyl ether and determination of the naproxen
by measuring the peak amplitude (mm) in the second-order
derivative spectrum at a wavelength of 328.2 nm. The efciency
of the extraction procedure expressed by the absolute recovery
was 94.6 0.7% (mean SD) for the concentration range
tested, and the LOQ attained according to the IUPAC denition was 2.42 lg mL1 (Panderi and Parissi-Poulou, 1994).

Table 4
161
Comparison between the spectrophotometric methods for determination of arylpropionic acids (profens).
Name of drug
Method
kmax (nm)
Ibuprofen
UV methods
200 and 400

220 and 231
Safranine
Kinetic method
Ketoprofen
Naproxen
First-derivative
Second-derivative
o-Chloranil
Linear range Ref.

(lg mL1)
2.412.0
240285
3001300
222
256
264 and 254.5
263.8 and 257.6
520
0.212.06
Khoshay et al. (2008)

Omry et al. (2007)
Sena et al. (2007)
Palabiyik et al. (2004)
Manikandan et al. (2001)
Sachan and Trivedi (1998)
Singhvi and Chaturvedi (1998a)
Singhvi and Chaturvedi (1998b)
Babu (1998)
Mitic et al. (2008)
234
El-Saharty et al. (2007)
Second-derivative
328.2
1-Naphthylarnine and sodium nitrite
460480
MBTH with Ce(VI) or Fe(III)
2,6-Dichloro-p-benzoquinone-4-chlorimine (gibbs reagent)
TCNE, DDQ, p-CHL
Tiaprofenic Acid Safranine-T
5.045
5.035
1080
1065
El-Sadek et al. (1993)

Panderi and Parissi-Poulou (1994)
Khan et al. (1999)
Hassan et al. (2008)
Jaiswal et al. (2007)
Duymus et al. (2006)
Vinci et al. (2006)
Naproxen reacts with 1-naphthylarnine and sodium nitrite

to give an orangish red colour having maximum absorbance
at 460480 nm (working wavelength 480 nm). The reaction is
selective for naproxen with 0.001 mg mL1 as visual LOQ
and provides a basis for a new spectrophotometric determination. The reaction obeys Beers law from 10 to 65 lg mL1 of
naproxen and the relative standard deviation is 1.5%. The
quantitative assessment of tolerable amount of other drugs is
also studied (Khan et al., 1999). Spectrophotometric methods
for the determination of naproxen based on the formation of a
coloured species with MBTH on oxidation with Ce(IV) or
Fe(III), are described (Sastry and Rao, 1989). Spectrophotometric method for the quantitative determination of naproxen,
after demethylation was developed based on the formation
of a coloured oxidative coupling product with 2,6-dichloro-pbenzoquinone-4-chlorimine (Gibbs reagent) in phosphate
buffer (pH 7.0). The reaction is sensitive to permit the determination of 5.0 lg mL1 (Sastry et al., 1988).
CT complexes of naproxen, which is electron donor with
some p-acceptors, such as tetracyanoethylene (TCNE), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), p-chloranil, have
been investigated spectrophotometrically in chloroform at
21 C. The coloured products are measured spectrophotometrically at different wavelength depending on the electronic
transition between donors and acceptors. Beers law is obeyed
and colours were produced in non-aqueous media. All complexes were stable at least 2.0 h except for etodolac with
DDQ stable for 5.0 min. The equilibrium constants of the
CT complexes were determined by the BenesiHildebrand
equation. The thermodynamic parameters DH, DS, DG were
calculated by Vant Hoff equation (Duymus et al., 2006).
The spectrophotometric method for the determination of

tiaprofenic acid was described. The method depends on the
determination of the drug after extraction as an ionassociation complex with safranine-T in chloroform at pH 7.4 (Ali
et al., 1994).
Table 4 shows comparison between the published spectrophotometric and spectrouorometric methods for profens.
5.5. Tiaprofenic acid
This review presents spectrophotometric and spectrouorometric analytical methods applied for the determination of
some non-steroidal anti-inammatory drugs, (coxibs,
arylalkanoic acids, N-arylanthranilic acids (fenamic acids)
and 2-arylpropionic acids (profens)) between 1985 and 2008.
The ofcial method of tiaprofenic acid was potentiometric

2004).
6. Applications
The above mentioned methods have applications in the determination of the studied drugs in various pharmaceutical formulations like tablets, suppositories, injections, capsules and
oral solutions. These methods give results which are comparable with the ofcial pharmacopoeial methods used for the
determination of the studied non-steroidal anti-inammatory;
hence, these methods can be successfully used for routine analysis and quality control of non-steroidal anti-inammatory
drugs. The methods have been used for the quantitative determination of the drug in pure form and commercial preparations. Human urine samples and serum samples have also
been successfully analyzed for the studied non-steroidal antiinammatory drugs by these methods. The commonly occurring exicipients do not interfere in the determination of the
drug in the case of commercial samples. The methods have
been validated statistically compared with the ofcial methods
by applying students t-test and F-value. The results have been
found to be accurate, precise and comparable to the ofcial
methods.
7. Conclusions
162
Spectrophotometric methods in UVvis (classical and for
consecutive derivatives) as well as uorometric are also quite
common, being most frequently used for quantication or conrmation of substance identity. Despite wide availability of the
equipment, their use is however still limited, especially with a
complicated matrix. The ultimate goal is to obtain results with
more and more precision and accuracy and at increasingly
lower concentration levels of the substances being determined.
This also facilitates the course of analysis by reducing the
impact of the matrix, without prior labour-consuming preparation of the samples (especially the biological ones). Comparing validation parameters of already researched methods, it
can be concluded which one of them is more sensitive (low
LOD and LOQ values), accurate (precision and recovery)
and allows markings in a broad linearity scope.
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NSAID Determination

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NSAID Determination

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Arabian Journal of Chemistry (2013) 6, 145163

King Saud University

Arabian Journal of Chemistry

Spectrophotometric and spectrouorometric methods

Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt

Received 27 June 2010; accepted 6 December 2010

* Corresponding author. Tel.: +2 055 242 3346; fax: +2 055 230

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A.A. Gouda et al.

NSAID molecules contain hydrophilic groups (carboxylic

Spectrophotometric and spectrouorometric methods

2. Spectrophotometric and spectrouorometric methods for

A.A. Gouda et al.

Spectrophotometric and spectrouorometric methods

Comparison between the spectrophotometric methods for determination of coxibs.

Sankar et al. (2007)

Aditya et al. (2006)

279, 228, 256 and 308

Erk and Altuntas (2004)

Duran et al. (2004)

Shakya and Khalaf (2007)

3. Spectrophotometric and spectrouorometric methods for

A.A. Gouda et al.

Spectrophotometric and spectrouorometric methods

A.A. Gouda et al.

Spectrophotometric and spectrouorometric methods

A.A. Gouda et al.

Name of drug Method

Nikam et al. (2007)

277, 295 (isobestic

3,3-Trimethyl-5-thiocyanato-2[3-(10 ,30 ,30 -trimethyl-30 -H-indol-20 -ylidene)-propenyl]indolium chloride (TIC)

El-Saharty et al. (2002)

Ghasemi et al. (2005a)

Ghiasvet al. (2008)

Matin et al. (2005)

Ortega-Barrales et al. (1999)

Arancibia et al. (2000)

Spectrophotometric and spectrouorometric methods

Gouda and Hassan (2008)

Amer et al. (2005)

Shingbal and Naik (1997)

Eid et al. (2007)

excipients. The RSD was 0.82% with recoveries 97102%

A.A. Gouda et al.

Spectrophotometric and spectrouorometric methods

A.A. Gouda et al.

4.3. Enfenamic acid

4.4. Tolfenamic acid

The ofcial method of enfenamic acid was potentiometric

The ofcial method of tolfenamic acid was potentiometric

Garg et al. (2007)

Sastry and Rao (1989)

Hassib et al. (1986)

Garcia et al. (2001)

Ioannou et al. (1998)

Sabry and Mahgoub (1999)

Khier et al. (1987)

Sastry et al. (1988)

Copper(II) ammine sulphate/

Ioannou et al. (1998)

Spectrophotometric and spectrouorometric methods

A.A. Gouda et al.

Spectrophotometric and spectrouorometric methods

200 and 400